Substituted 1-(oxopyrrolidinylalkanoyl)-piperazines useful as nootropics

- Ciba-Geigy Corporation

Substituted pyrrolidin-2-ones of the formula ##STR1## wherein R.sub.1 represents a phenyl or naphthyl radical that is unsubstituted or substituted by lower alkyl, lower alkloxy, halogen and/or trifluoromethyl, X.sub.1 represents lower alkylidene, X.sub.2 represents methylene, ethylene or oxoethylene and R.sub.2 represents hydrogen, lower alkyl or a radical of the formula ##STR2## wherein X.sub.4 represents lower alkylidene and R.sub.3 represents hydrogen or a phenyl or a phenyl naphthyl radical that is unsubstituted by lower alkyl, lower alkoxy, halogen and/or trifluoromethyl, and their pharmaceutically acceptable salts, have nootropic properties and can be used as nootropic active ingredients in medicaments. They are prepared, for example, by condensing with one another compounds of the formulae ##STR3## wherein Z.sub.1 represents a group of the formula --X.sub.1 --(.dbd.O)--Z.sub.3 (IIa) and Z.sub.2 represents hydrogen, or Z.sub.1 represents hydrogen and Z.sub.2 represents a group of the formula --C(.dbd.O) --X.sub.1 --Z.sub.4 (IIIa), wherein each of Z.sub.3 and Z.sub.4 represents a removable radical and R.sub.2 ' represnts a radical R.sub.2 or amino-protecting group, or their salts, and removing an amino-protecting R.sub.2 ' which may be present.

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Description
EXAMPLE 1

82.5 g (325 mmol) of 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid, 32.5 g (325 mmol) of piperazin-2-one (ketopiperazine) and 100.8 g (325 mmol) of freshly distilled triphenyl phosphite are melted at 180.degree.. The whole is allowed to cool to 130.degree. and left to stand for 5 hours. The solidified reaction mass is cooled to room temperature and stirred for 1 hour with 300 ml of dichloromethane. The whole is filtered with suction, washed three times with 150 ml of dichloromethane each time and allowed to dry in the air. 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-3-oxopiperazine having a melting point of 208.degree.-210.degree. is obtained and can be purified further by dissolving in 200 ml of hot acetic acid, adding 800 ml of water and crystallising in an ice bath.

The starting material can be manufactured, for example, as follows:

13 g (565 mmol) of sodium are added in portions to 410 ml of ethanol. After it has dissolved completely, 107 g (545 mmol) of 4-(p-chlorophenyl)-2-oxopyrrolidine are added, the whole is stirred at room temperature for 2 hours, concentrated to dryness by evaporation under reduced pressure and dried overnight at 100.degree. under reduced pressure. The resulting sodium 4-(p-chlorophenyl)-2-oxopyrrolidine is made into a slurry in 340 ml of toluene, and a solution of 63.7 ml (95.9 g; 574 mmol) of bromoacetic acid ethyl ester is added dropwise, while stirring, at 20.degree. to 25.degree.. The whole is stirred for a further 16 hours, concentrated to dryness by evaporation under reduced pressure at approximately 70.degree. and partitioned between 300 ml of water and 600 ml of ethyl acetate. The organic phase is separated off, washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness by evaporation under reduced pressure. 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid ethyl ester is obtained which, for purification, is distilled under reduced pressure; b.p.=176.degree.-178.degree. at 0.02 torr (0.027 mbar).

95.6 g (340 mmol) of 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid ethyl ester are dissolved in 440 ml of methanol; 22.5 g (40 mmol) of potassium hydroxide (80% strength) are added and the whole is heated under reflux for 16 hours. Concentration by evaporation is carried out under reduced pressure at 70.degree., 200 ml of hydrochloric acid are added and the whole is extracted by shaking with 800 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride solution, concentrated to 500 ml, and 200 ml of hexane are added. The crystalline precipitate is filtered off with suction and dried. 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid having a melting point of 142.degree.-43.degree. is obtained. Additional product can be obtained by concentrating the mother liquor by evaporation, taking up the residue in 200 ml of ethyl acetate and crystallising it by the addition of 100 ml of hexane.

EXAMPLE 2

4.46 g (44.6 mmol) of piperazin-2-one (ketopiperazine) and 300 ml of dimethylformamide are added to 22.4 g (44.6 mmol) of 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid pentachlorophenyl ester and the whole is stirred for 5 hours at room temperature. The whole is concentrated to dryness by evaporation under reduced pressure at 70.degree., stirred with 150 ml of ethyl acetate for 1 hour and then 150 ml of diethyl ether are added; the whole is filtered with suction, washed with 50 ml of diethyl ether and allowed to dry. 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-3-oxopiperazine having a melting point of 205.degree.-207.degree. is obtained and can be purified further by recrystallisation from 300 ml of butanol, washing with 50 ml of diethyl ether and drying, and then melts at 208.degree.-210.degree..

The starting material can be manufactured, for example, as follows:

73.5 g (290 mmol) of 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid are suspended in 900 ml of tetrahydrofuran; 92.5 g (350 mmol) of pentachlorophenol are added and the whole is stirred at room temperature until a clear solution is obtained. The solution is cooled in an ice bath, 65.8 g (319 mmol) of dicyclohexylcarbodiimide dissolved in 180 ml of tetrahydrofuran are added dropwise thereto within a period of 30 minutes and the whole is stirred for a further 1 hour in the ice bath and for a further 16 hours at room temperature; the resulting dicyclohexylurea is filtered off and the filtrate is concentrated to dryness by evaporation under reduced pressure at 60.degree. and recrystallised from 400 ml of ethyl acetate. 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid pentachlorophenyl ester having a melting point of 135.degree.-136.degree. is obtained. Additional product can be obtained by concentrating the mother liquor.

EXAMPLE 3

10 g (30 mmol) of N-[4-(p-fluorophenyl)-2-oxopyrrolidin-1-ylacetoxy]-succinimide and 3.0 g (30 mmol) of piperazin-2-one (ketopiperazine) are stirred at room temperature in 100 ml of dimethylformamide for 16 hours. The whole is concentrated to dryness by evaporation at 70.degree. under reduced pressure, extracted at boiling temperature with trichloromethane, allowed to cool, filtered with suction and allowed to dry in the air. 1-[4-(p-fluorophenyl)-2-oxopyrrolidin-1-ylacetyl]-3-oxopiperazine having a melting point of 200.degree.-203.degree. is obtained.

The starting material can be manufactured, for example, as follows:

A total of 31.5 g (150 mmol) of dicyclohexylcarbodiimide is added in portions to a solution of 35.6 g (150 mmol) of 2-[4-(p-fluorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid and 17.2 g (150 mmol) of N-hydroxysuccinimide in 570 ml of dioxan, during which operation the temperature of the reaction mixture should be maintained below 30.degree. by cooling in an ice bath. When the exothermic reaction has ceased, the reaction mixture is stirred for 16 hours at room temperature, the precipitated dicyclohexylurea is filtered off and the filtrate is concentrated to dryness by evaporation under reduced pressure at 70.degree.. The residue is dissolved in 200 ml of ethyl acetate, and diethyl ether is added until the solution starts to turn cloudy. The crystalline precipitate which forms directly is filtered off with suction, washed with diethyl ether and dried. N-[4-(p-fluorophenyl)-2-oxopyrrolidin-1-ylacetoxy]-succinimide having a melting point of 120.degree.-123.degree. is obtained.

EXAMPLE 4

A mixture of 10 g (3.7 mmol) of 2-[4-(p-chlorophenoyl)-2-oxopyrrolidin-1-yl]-acetic acid methyl ester and 10 g (100 mmol) of N-methylpiperazine is shaken until it turns red. The mixture is concentrated to dryness by evaporation under reduced pressure at 70.degree.. The oily residue (14.3 g) is dissolved in 100 ml of N hydrochloric acid and the solution is extracted with 100 ml of ethyl ether. The aqueous phase is rendered alkaline with concentrated sodium hydroxide solution and the base thus freed is extracted with 500 ml of methylene chloride. After drying over sodium sulphate, filtering and concentrating by evaporation, 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-4-methylpiperazine is obtained. The mass spectrogram indicates a molecular weight of 336.

9.9 g of the free base are dissolved in 30 ml of ethanol, adjusted to pH 4 with ethanolic hydrochloric acid and the hydrochloride formed is precipitated by the addition of ethyl ether and filtered with suction. 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-4-methylpiperazine bis-hydrochloride having a melting point of 202.degree.-204.degree. is obtained.

EXAMPLE 5

A solution of 15.8 g (50 mmol) of N-[2-(2-oxo-4-phenylpyrrolidin-1-yl)-acetoxy]-succinimide and 8.8 g (50 mmol) of N-benzylpiperazine in 100 ml of dimethylformamide is stirred at room temperature for 16 hours. The reaction mixture is freed of the solvent under reduced pressure at 70.degree.. The oily residue (28 g) is taken up in 100 ml of ethyl acetate, washed three times with 50 ml of water each time, extracted by shaking with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated to 30 to 40 ml. The aqueous extracts contain N-hydroxysuccinimide and are discarded. A solution of 5.8 g of maleic acid, dissolved in 100 ml of warm ethyl acetate, is added to the concentrated ethyl acetate layer. The resulting salt first precipitates in the form of an oil but crystallises fully when stirred in an ice bath. After recrystallisation from ethanol, crystalline 1-(2-oxo-4-phenylpyrrolidin-1-ylacetyl)-4-benzylpiperazine maleate having a melting point of 170.degree.-173.degree. is obtained.

19 g of the salt described are made into a slurry with 100 ml of water, covered with a layer of 100 ml of ethyl acetate, and adjusted to pH 8 to 9 with saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer is washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness by evaporation. Oily 1-[2-(2-oxo-4-phenylpyrrolidin-1-yl)-acetyl]-4-benzylpiperazine having an Rf value of 0.60; eluant toluene/ethanol (1:1), is left behind as the residue.

The oily base is taken up in 300 ml of acetic acid and hydrogenated for 16 hours at 22.degree. in the presence of 1.5 g of 5% palladium-on-carbon. After 860 ml of hydrogen have been absorbed the catalyst is filtered off and the clear filtrate is concentrated to dryness by evaporation under reduced pressure at 70.degree.. The oily residue crystallises when digested with ethyl acetate in an ice bath and is recrystallised from 200 ml of ethyl acetate. 1-[2-(2-oxo-4-phenylpyrrolidin-1-yl)-acetyl]-piperazine diacetate having a melting point of 121.degree.-124.degree. is obtained.

EXAMPLE 6

To a suspension of 6.0 g (23.3 mmol) of 1-[2-(2-oxopyrrolidin-1-yl)-acetyl]-piperazine hydrochloride in 80 ml of methylene chloride there are added firstly 2.6 g (3.6 ml; 25.5 mmol) of triethylamine and then, dropwise, a solution of 13.7 g (23.3 mmol) of 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid pentachlorophenyl ester in 30 ml of methylene chloride. After being stirred at 20.degree. for 16 hours, the suspension is filtered with suction. 6.16 g of a white crystalline mass are obtained. 110 ml of ethyl ether are stirred into the filtrate, whereby a further 6.51 g of precipitate can be formed and collected. The two portions are combined, triturated under 200 ml of ethyl ether and filtered with suction, and the resulting product is dissolved in 150 ml of hot glacial acetic acid, and warm water (50.degree.) is added until the solution becomes cloudy. The whole is cooled to 20 .degree.; after 3 hours, the resulting crystalline product is filtered off with suction and dried on a water bath. 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-4-(2-oxopyrrolidin1-ylac etyl)-piperazine having a melting point of 224.degree.-226.degree. is obtained.

The starting material can be manufactured, for example, as follows:

A solution of 14.4 g (60 mmol) of N-[2-(2-oxopyrrolidin-1-yl)-acetoxy]-succinimide and 10.6 g (60 mmol) of 1-benzylpiperazine in 125 ml of dimethylformamide is stirred for 16 hours at 20.degree.. The reaction mixture is concentrated to dryness by evaporation under reduced pressure at 90.degree.. The oily residue is taken up in 250 ml of water, and a solution of 5.4 g of oxalic acid in 5 ml of water is added, and then the whole is stirred in an ice bath. The resulting crystalline oxalate is filtered off with suction, dissolved in 400 ml of water and the pH is adjusted to 9 with concentrated ammonia solution The clear aqueous solution is washed twice with 30 ml of ether each time, the ethereal extracts are discarded and the aqueous layer is concentrated by evaporation under reduced pressure at 70.degree.. The residue is composed of a sticky mass which is stirred into 400 ml of ethanol at 30.degree. and the insoluble matter is filtered off with suction. After concentrating the clear ethanolic filtrate by evaporation, a slightly yellowish oil is obtained. This is boiled in 130 ml of ethyl acetate and filtered while hot, and the filtrate is stirred in an ice bath to complete the reaction. The precipitated crystals are filtered off with suction and dried on a water bath. 1-[2-(2-oxopyrrolidin-1-yl)-acetyl]-4-benzylpiperazine is obtained.

A solution of 13.2 g of this product in 300 ml of glacial acetic acid is hydrogenated for 4 hours at 20.degree. in the presence of 1.5 g of 5% palladium-on-carbon. After 986 ml of hydrogen have been absorbed, the hydrogenation is discontinued, the catalyst is filtered off with suction and the filtrate is concentrated to dryness by evaporation under reduced pressure at 70.degree. The oily residue is dissolved in 200 ml of ethyl acetate and the pH is adjusted to 2 with alcoholic hydrochloric acid. The resulting hydrochloride is filtered off with suction and recrystallised from ethanol. 1-[2-(2-oxopyrrolidin-1-yl)-acetyl]piperazine hydrochloride having a melting point of 232.degree.-234.degree. is obtained. The maleate which can be prepared analogously melts at 163.degree.-165.degree..

EXAMPLE 7

A mixture of 5.1 g (20.1 mmol) of 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid, 3.5 g (20.1 mmol) of 1-benzylpiperazine, 6.57 g (21.1 mmol) of triphenyl phosphite and 15 ml of dimethylformamide is stirred for 3 hours at 95.degree.-100.degree.. The mixture is the concentrated under reduced pressure at 90.degree. until a constant weight is reached. The oily residue is diluted with 40 ml of acetone, and a solution of 2.3 g of maleic acid in 20 ml of acetone is added thereto. The precipitated maleate is filtered off with suction and washed with a little acetone and ethyl ether. The resulting 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-4-benzylpiperazine maleate having a melting point of 161.degree.-164.degree. is recrystallised from methanol and ether.

14.3 g of the base freed from the maleate are catalytically debenzylated in 150 ml of glacial acetic acid with hydrogen in the presence of 1.5 g of 5% palladium-on-carbon. After 777 ml of hydrogen have been absorbed, the catalyst is filtered off with suction and the filtrate is concentrated by evaporation under reduced pressure at 80.degree.. 60 ml of water and 40 ml of N sodium hydroxide solution are added to the oily residue and the whole is extracted twice with 50 ml of chloroform each time. After drying over sodium sulphate, filtering and concentrating by evaporation, 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-piperazine is obtained in the form of a yellowish oil which is dissolved in 100 ml of acetone and is converted into the maleate having a melting point of 148.degree.-150.degree. by the addition of 3.4 g of maleic acid.

EXAMPLE 8

7.74 g (25 mmol) of 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-4-methylvaleric acid, 2.75 g (27.5 mmol) of piperazin-2-one and 0.3 g (2.5 mmol) of 4-methylaminopyridine are dissolved in 100 ml of tetrahydrofuran, and a solution of 5.67 g (27.5 mmol) of N,N'-dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran is added dropwise, while stirring, at a temperature of from 10.degree. to 15.degree.. The suspension is stirred for 16 hours at room temperature.

The crystals are filtered off with suction, the filtrate is concentrated by evaporation under reduced pressure, and the oily residue is dissolved in 100 ml of methylene chloride and washed twice with 50 ml of hydrochloric acid each time, twice with sodium hydrogen carbonate solution and twice with 50 ml of water each time. The organic phase is separated off, dried over sodium sulphate, filtered and concentrated to dryness by evaporation under reduced pressure. The product is purified by flash column chromatography. 1-{2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-4-methylpentanoyl}-3-oxopip erazine is obtained in the form of a foam.

The starting material can be manufactured, for example, as follows:

4.8 g (208 mmol) of sodium are added in portions to 150 ml of ethanol. After it has dissolved completely, 39.15 g (200 mmol) of 4-(p-chlorophenyl)-2-oxopyrrolidine are added and the whole is stirred for 2 hours at room temperature, concentrated to dryness by evaporation under reduced pressure, made into a slurry 3 times with toluene and concentrated to dryness by evaporation under reduced pressure.

The resulting sodium salt of 4-(p-chlorophenyl)-2-oxopyrrolidone is made into a slurry in 200 ml of toluene, and a solution of 40.2 g (191.3 mmol) of 2-bromo-4-methylvaleric acid methyl ester in 50 ml of toluene is added dropwise, while stirring, at from 20 to 25.degree.. The whole is stirred for a further 16 hours, concentrated to dryness by evaporation under reduced pressure at approximately 50.degree. and partitioned between 200 ml of water and 300 ml of ethyl acetate. The organic phase is separated off, washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness by evaporation under reduced pressure 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-4-methylvaleric acid methyl ester is obtained which, for purification, is distilled under reduced pressure in a bulb tube. B.p.=200.degree. at 0.1 torr.

53.3 g (164.6 mmol) of 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-4-methylvaleric acid methyl ester are dissolved in 230 ml of methanol; 10.9 g (164.4 mmol) of potassium hydroxide (85% strength) are added and the whole is heated under reflux for 16 hours. The whole is concentrated by evaporation under reduced pressure at 50.degree., 230 ml of 2N hydrochloric acid are added, and the resulting suspension is stirred for 1 hour at 5.degree.. The crystals are filtered off with suction, washed with water and dried under reduced pressure at 80.degree.. Recrystallisation from ethyl acetate/hexane yields 46.1 g of 2-[4-p-chlorophenyl)-2-oxopyrrolidin-1-yl]- 4-methylvaleric acid; m.p. 176.degree.-177.degree..

EXAMPLE 9

It is also possible to manufacture 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-4-methyl-3-oxopiperazine in a manner analogous to that described in Examples 1 to 7.

EXAMPLE 10

1.77 g of 1-chloroacetyl-3-oxopiperazine are suspended in 500 ml of toluene at 80.degree.. A total of 2.18 g of sodium-4-(p-chlorophenyl)-2-oxopyrrolidin-2-one is then added in three portions. The whole is stirred for 8 hours at 80.degree. and concentrated to dryness by evaporation under reduced pressure at 70.degree., and a secondary product is distilled off at 150-.degree.155.degree./0.05 torr; the residue is extracted by boiling with butanol, filtered and concentrated to dryness by evaporation 1.5 g of 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-3-oxopiperazine having a melting point of 208.degree.-210.degree. are obtained.

EXAMPLE 11

Tablets each containing 50 mg of 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-3-oxopiperazine can be manufactured as follows:

  ______________________________________                                    
     Composition (1000 tablets)                                                
     ______________________________________                                    
     Active ingredient       500.0 g                                           
     Lactose                 500.0 g                                           
     Potato starch           352.0 g                                           
     Gelatine                8.0 g                                             
     Talc                    60.0 g                                            
     Magnesium stearate      10.0 g                                            
     Silica (highly disperse)                                                  
                             20.0 g                                            
     Ethanol                 q.s.                                              
     ______________________________________

The active ingredient is mixed with the lactose and 292 g of potato starch and the mixture is moistened with an alcoholic solution of the gelatine and granulated through a sieve. After drying, the remainder of the potato starch, the talc, the magnesium stearate and the highly disperse silica are mixed in and the mixture is compressed to form tablets each weighing 145.0 mg and containing 50.0 mg of active ingredient, which, if desired, can be provided with dividing notches for finer adjustment of the dosage.

EXAMPLE 12

Lacquer-coated tablets each containing 100 mg of 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl-acetyl]-3-oxopiperazine can be manufactured as follows:

  ______________________________________                                    
     Composition (for 1000 tablets)                                            
     ______________________________________                                    
     Active ingredient       100.00 g                                          
     Lactose                 100.00 g                                          
     Corn starch             70.00 g                                           
     Talc                    8.50 g                                            
     Calcium stearate        1.50 g                                            
     Hydroxypropylmethylcellulose                                              
                             2.36 g                                            
     Shellac                 0.64 g                                            
     Water                   q.s.                                              
     Methylene chloride      q.s.                                              
     ______________________________________

The active ingredient, the lactose and 40 g of the corn starch are mixed and moistened with a paste prepared from 15 g of corn starch and water (while heating), and granulated. The granulate is dried and the remaining corn starch, the talc and the calcium stearate are added and mixed with the granulate. The mixture is compressed to form tablets (weight: 280 mg) and these are coated with a solution of the hydroxypropylmethylcellulose and the shellac in methylene chloride; final weight of the lacquer-coated tablets: 283 mg.

EXAMPLE 13

In a manner analogous to that described in Examples 11 and 12 it is also possible to manufacture pharmaceutical preparations containing a different compound of the formula I according to Examples 1 to 9.

Claims

1. A compound of the formula ##STR18## wherein R.sub.1 represents a phenyl or naphthyl that is unsubstituted or mono- or di-substituted by at least one of lower alkyl, lower alkoxy, halogen and trifluoromethyl, X.sub.1 represents lower alkylidene, X.sub.2 represents ethylene or oxoethylene and R.sub.2 represents hydrogen, lower alkyl or a radical of the formula ##STR19## wherein X.sub.4 represents lower alkylidene and R.sub.3 represents hydrogen or phenyl or naphthyl that is unsubstituted or mono- or di-substituted by at least one of lower alkyl, lower alkoxy, halogen and trifluoromethyl, in free form or in the form of pharmaceutically acceptable salt.

2. A compound according to claim 1 of the formula I, wherein R.sub.1 represents phenyl or naphthyl that is unsubstituted or mono- or di-substituted by at least one of C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, halogen having an atomic number of up to and including 35 and by trifluoromethyl, X.sub.1 represents C.sub.1 -C.sub.7 -alkylidene, X.sub.2 represents ethylene or oxoethylene and R.sub.2 represents hydrogen, C.sub.1 -C.sub.7 -alkyl or a group of the formula Ia wherein X.sub.4 represents C.sub.1 -C.sub.7 -alkylidene and R.sub.3 represents hydrogen or phenyl or naphthyl that is unsubstituted or mono- or di-substituted by at least one of C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, halogen having an atomic number of up to and including 35 and by trifluoromethyl, or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 of the formula I, wherein R.sub.1 represents phenyl that is unsubstituted or mono substituted by halogen having an atomic number of up to and including 35, C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -alkyl or by trifluoromethyl, or represents unsubstituted naphthyl, X.sub.1 represents terminally bonded C.sub.1 -C.sub.7 -alkylidene, X.sub.2 represents oxoethylene and R.sub.2 represents hydrogen, or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1 of the formula I, wherein R.sub.1 represents phenyl that is unsubstituted or monosubstituted by halogen having an atomic number of up to and including 35, C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -alkyl or by trifluoromethyl, or represents unsubstituted naphthyl, X.sub.1 represents terminally bonded C.sub.1 -C.sub.4 -alkylidene, X.sub.2 represents oxoethylene bonded via the carbonyl group to the partial structure --N(R.sub.2)-- and R.sub.2 represents hydrogen, or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1 of the formula I, wherein R.sub.1 represents phenyl that is unsubstituted or substituted by halogen having an atomic number of up to and including 35, C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -alkyl or by trifluoromethyl, or represents unsubstituted naphthyl, X.sub.1 represents terminally bonded C.sub.1 -C.sub.4 -alkylidene, X.sub.2 represents ethylene and R.sub.2 represents C.sub.1 -C.sub.4 -alkyl or a group of the formula Ia wherein X.sub.4 is terminally bonded C.sub.1 -C.sub.4 -alkylidene, and R.sub.3 represents hydrogen, or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 of the formula I, wherein R.sub.1 represents phenyl that is unsubstituted or monosubstituted by halogen having an atomic number of up to and including 35 or represents unsubstituted naphthyl, X.sub.1 represents terminally bonded C.sub.1 -C.sub.4 -alkylidene, X.sub.2 represents oxoethylene bonded via the carbonyl group to the partial structure --N(R.sub.2)-- and R.sub.2 represents hydrogen, or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 of the formula I, wherein R.sub.1 represents phenyl that is unsubstituted or monosubstituted by halogen having an atomic number of up to and including 35 or represents unsubstituted naphthyl, X.sub.1 represents terminally bonded C.sub.1 -C.sub.7 -alkylidene, X.sub.2 represents oxoethylene bonded via the carbonyl group to the partial structure --N(R.sub.2)-- and R.sub.2 represents hydrogen, or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 being 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-3-oxopiperazine or a salt thereof.

9. A compound according to claim 1 being 1-[4-(p-fluorophenyl)-2-oxopyrrolidin-1-ylacetyl]-3-oxopiperazine or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 1 being 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-4-methylpiperazine or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 1 being 1-[2-oxo-4-phenylpyrrolidin-1-ylacetyl)-4-benzylpiperazine or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1 being 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-4-(2-oxopyrrolidin-1-yla cetyl)-piperazine or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 1 being 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-4-benzylpiperazine or a pharmaceutically acceptable salt thereof.

14. A compound according to claim 1 being 1-{2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-4-methylpentanoyl}-3-oxopip erazine or a pharmaceutically acceptable salt thereof.

15. A compound according to claim 1 being 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-4-methyl-3-oxopiperazine or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a nootropically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in addition to customary pharmaceutical adjuncts.

17. Method for the treatment of cerebral insufficiency in human or animal body comprising administering a nootropically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

Referenced Cited
U.S. Patent Documents
3459738 August 1969 Morren
4144246 March 13, 1979 L'Italien
Other references
  • CA 95:24693r (1981).
Patent History
Patent number: 4945092
Type: Grant
Filed: Jun 19, 1989
Date of Patent: Jul 31, 1990
Assignee: Ciba-Geigy Corporation (Ardsley, NY)
Inventors: William Bencze (Therwil), Wolfgang Frostl (Basel), Max Wilhelm (Riehen)
Primary Examiner: Cecilia Shen
Attorney: JoAnn Villamizar
Application Number: 7/370,093
Classifications
Current U.S. Class: 514/252; Five-membered Hetero Ring Consisting Of One Nitrogen And Four Carbons (544/372)
International Classification: A61K 31495; C07D40312; C07D40314;